title: Mammalian target of rapamycin inhibitor rapamycin enhances anti-leukemia effect of imatinib on Ph+ acute lymphoblastic leukemia cells.
abstract: BCR-ABL fusion gene typically causes a type of acute lymphoblastic leukemia (ALL), known as Ph+ ALL. Although imatinib (IM) treatment induced high rates of complete response (CR), serious acute and late complications are frequent, whereas more vexatiously resistance to chemotherapy and clinical relapse develops. Therefore, the efficacy of treatment in Ph+ ALL is still to be determined. In this study, we focused our attention on the potential benefit of rapamycin (RAPA), an mammalian target of rapamycin (mTOR) inhibitor, in combination with IM on a Ph+ ALL cell line SUP-B15 and a primary Ph+ ALL sample in vitro. Analysis of cell proliferation showed that RAPA (50 nm) plus IM exerted good synergistic effect on Ph+ ALL cells. Notably, we found that IM treatment induced the abnormal activation of the components of mTOR signaling pathway and p-BCR-ABL, whereas RAPA potently eliminated this deleterious side effect induced by IM and might overcome the resistance to IM. The synergistic effect was also associated with the increase in autophagy, which seemed to have an opposite role with apoptosis in Ph+ ALL cells, and cell cycle arrest in G1 phase. Altogether, our results suggested that IM in combination with RAPA was more effective for Ph+ ALL cells than IM alone.
authors.affiliation: Department of Hematology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Guangcui
authors.initials: G
authors.lastname: He
authors.forename: Yuping
authors.initials: Y
authors.lastname: Gong
authors.forename: Bohui
authors.initials: B
authors.lastname: Zheng
authors.forename: Fangfang
authors.initials: F
authors.lastname: Shi
authors.forename: Rui
authors.initials: R
authors.lastname: Shi
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Ph+ acute lymphoblastic leukemia; autophagy; imatinib; mammalian target of rapamycin signaling pathway; rapamycin